Parenteral controlled therapy, using a porous matrix with parenteral agent

ABSTRACT

A parenteral delivery set is disclosed for administering a beneficial agent to a recipient. The set comprises (a) a primary container of a medical fluid; (b) a primary tubing in fluid communication with the primary container; (c) a secondary container of a medical fluid; (d) a secondary tubing in fluid communication with the secondary container; (e) a formulation chamber connected to the secondary tubing and housing an agent dispensing device or the beneficial agent; and (f) a common tubing in communication with the primary tubing and the secondary tubing for communicating the set to the recipient.

CROSS-REFERENCE TO COPENDING APPLICATIONS

This application is a division of U.S. patent application Ser. No.06/542,466, filed Oct. 17, 1983, now U.S. Pat. No. 4,493,702, issued onJan. 15, 1985, which is a continuation of U.S. patent application Ser.No. 06/325,206 filed on Nov. 27, 1981, now U.S. Pat. No. 4,432,756,issued on Feb. 21, 1984. These applications are assigned to ALZACorporation of Palo Alto, Calif., and benefit is claimed of their filingdates.

FIELD OF THE INVENTION

This invention pertains to a parenteral delivery system. The systemcomprises a primary path and a secondary path comprising a formulationchamber containing (1) an agent delivery device, or (2) a beneficialagent. The invention relates also to a method of administeringparenterally an agent using the parenteral delivery system.

BACKGROUND OF THE INVENTION

The parenteral administration of sterile fluid is an establishedclinical practice, and the practice is used extensively as an integralpart of the daily treatment of medical and surgical patients. The fluidsadministered parenterally, usually intravenously, include aqueoussolutions of dextrose, solium chloride, and various other electrolytes.Always administered intravenously are blood and blood substitutes.Generally, the fluids are administered from a container that issuspended above a patient, with the fluid flowing from the containerthrough an administration set and thence to a cannula or a hypodermicneedle placed in a blood vessel, usually a vein of the patient. Forintraperitoneal administration of fluids, the administration set isconnected to a cannula traversing the abdominal wall of the patient.

The administration of fluids parenterally is a valuable and importantcomponent of patient care. The use of parenteral fluids moreover has inrecent years expanded beyond its original role of fluid and electrolytereplacement to include serving as the vehicle for the parenteraladministration of beneficial agents, notably for those where it isdesirable to administer by infusion via the intravenous, intra-arterial,intrapertioneal or subcutaneous routes. For example, presently abeneficial agent, such as a drug, is administered intravenously by oneof the following procedures: temporarily halting the flow of medicalfluid and intravenously administering a solution of the drug to thepatient through an injection port in the administration set, followed byresumption of medical fluid into the patient; a drug is added to thefluid in the container, or into a volume control chamber in series withthe administration set, and then carried by the flow of fluid into thepatient; a drug is introduced into a so-called "piggyback" container,which is subsequently connected via a connector, in tributary fashion,to the primary administration set through which fluid is administered tothe patient; or a drug is administered by a pump which, by one ofvarious recognized pumping actions, establishes flow and this determinesthe flow of fluid containing the drug into a flow path entering thepatient, for example, an indwelling venous catheter.

While these techniques are widely used, they have certain inherentdisadvantages. For example, the administration of a drug throughrepeated injections into the administration set is inconvenient andrepresents each time a potential break in sterility; the use of pumps isexpensive and sometimes inconvenient because of their size and weight;the rate of drug delivery to the patient is dependent on the flow offluid with all currently practiced means of drug infusion; because ofthe relative chemical instability of aqueous solutions of manyparenteral drugs, these procedures often require solubilization of thedrug medication by the hospital pharmacist or by the nurse at a timeproximate to its administration; and, while it is current practice togive some drugs by brief infusions, typically of 30 to 120 minutesduration repeated 3 or 4 times a day, they do not provide a means for(a) careful coordination of the procedures for solubilization andadministration, (b) careful regulation of the flow of drug solutionduring each period of infusion to insure that infusion is completedwithin the recommended time, and (c) for doses prepared in advance andadministered at a preselected time.

In view of this presentation, it is immediately apparent a critical needexists for a dependable and practicable parenteral therapeutic deliverysystem that overcomes the disadvantages associated with the systemsknown to the prior art. It is also apparent that a pressing need existsfor a parenteral delivery system that can be used clinically foradministering parenterally a beneficial agent at a controlled rate andin a beneficially effective amount to a patient according to apreselected program comprising continuous administration, repeatedadministration, administration at specified intervals, or as neededadministration.

DISCLOSURE OF THE INVENTION

Accordingly, a principle object of this invention is to provide both anovel and useful parenteral delivery system for administering a fluidand a beneficial agent at a controlled rate and according to a chosenregimen of administration and in an improved manner for optimizing thecare of a warm-blooded animal whose prognosis benefits from parenteraladministration.

Another object of the invention is to provide a parenteral deliverysystem comprising (1) a primary fluid path, and (2) a secondary fluidpath comprising a formulation chamber containing (a) an agent deliverydevice for delivering an agent into a medical fluid that flows into thechamber, or (b) a beneficial agent, which agent in either instance formsin situ an agent solution for administration to an animal, including ahuman patient.

Another object of this invention is to provide a delivery systemcomprising (1) a primary fluid path and (2) a secondary fluid pathhaving a formulation chamber, and which system can be used for improvedhealth care by making available to the practitioner (a) a mechanism foradministering a fluid via the primary path, (b) a mechanism foradministering a fluid containing a beneficial agent via the secondarypath, and (c) a mechanism for controlling the volume and theconcentration of agent administered by adjusting the rate of flowthrough the primary path and by adjusting concomitantly the rate of flowthrough the secondary path prior to their mixing into a single fluid forits subsequent administration.

Another object of this invention is to provide a parenteral deliverysystem that comprises a means for automatically constituting an agentformulation in situ by dissolving a given amount of agent in a givenvolume of fluid that can be administered at any selected time, includingintermittent intravenous therapy.

Another object of this invention is to provide a parenteral deliverysystem that makes attainable a program of agent administration adaptedto a specific need by furnishing an agent formulation comprising a knownvolume of fluid containing from a trace to a saturating amount of abeneficial agent that can be administered at any chosen time.

Another object of this invention is to provide a parenteral deliverysystem that makes possible a means for converting a continuouslyfunctioning process of agent formulation and release into a method ofagent administration that occurs at predetermined periods according to aspecified rate and duration of agent administration.

Another object of this invention is to provide a parenteral deliverysystem that makes available a regimen of agent administration comprisingintervals of agent administration at a specified rate and for aspecified duration, alternating with intervals during which no agent isdelivered by the system.

This invention concerns a parenteral delivery system for theadministration of a medical fluid containing a beneficial agent to ananimal, including a human patient. The system comprises: (1) a primaryfluid path consisting of a container of medical fluid and a primary tubethat communicates from the container to a common tube that leads to aninfusion site in the animal; (2) a secondary fluid path consisting of aminicontainer of a medical fluid in fluid communication with an agentformulation chamber. The formulation chamber comprises: (a) a wallsurrounding a lumen and has a surface that permits communication withthe secondary path to let a fluid flow from the container into theformulation chamber; (b) a delivery device containing a beneficial agentthat is released into the formulation chamber, or a beneficial agent inthe formulation chamber, which agent in either instance forms an agentformulation with fluid that enters the formulation chamber; and (c) anoutlet surface that lets agent formulation leave the formulation chamberand enter the secondary path and then into the common path foradministration to the patient. The system additionally comprises amechanism that can optionally be used for converting a continuouslyfunctioning process of agent formulation and releasing into (d) thecommon flow path so that agent administration into the patient occursduring quantitatively predetermined intervals according to a specifiedrate and duration of agent infusion, or (e) from the formulation chamberinto a regimen of agent administration to the patient characterized byintervals of agent infusion at a specified rate and specified durationalternating with intervals during which no agent reaches the infusionsite in the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale but are set forth toillustrate various embodiments of the invention, the Figures are asfollows:

FIG. 1 is a perspective view of a parenteral delivery system provided bythe invention;

FIG. 2 is a view illustrating another embodiment of the parenteraldelivery system;

FIG. 3 is a view of yet another embodiment of the parenteral deliverysystem;

FIG. 4 is a view of an agent formulation chamber adapted for use in theparenteral delivery system, with the chamber housing an osmotic agentdelivery device;

FIG. 5 is a view of an agent delivery device comprising a release ratecontrolling membrane surrounding a reservoir containing a beneficialagent which device is adapted for use in an agent formulation chamber;

FIG. 6 is a view of a delivery device comprising a release ratecontrolling membrane surrounding a different reservoir containing abeneficial agent which device is designed for use in an agentformulation chamber;

FIG. 7 is a view of an agent delivery device comprising a microporousmembrane surrounding a reservoir containing a beneficial agent whichdevice can be used for the purpose of the invention in the formulationchamber;

FIG. 8 is a view of a delivery device comprising a matrix containing abeneficial agent which device can be used in the formulation chamber;

FIG. 9 is a view of a delivery device comprising a microporous matrixcontaining an agent which device can be used in the formulation chamberfor carrying out the invention;

FIG. 10 is a view of a delivery device comprising depots of agent whichdevice can be used in the formulation chamber;

FIG. 11 is a view of a delivery device comprising a housing and adriving member surrounding a flexible container that can be used in aformulation chamber;

FIG. 12 is an opened view of a formulation chamber comprising abeneficial agent and a release rate controlling membrane; and,

FIG. 13 is an opened view of an agent formulation chamber comprising abeneficial agent, a release rate controlling membrane and a filter.

In the specification and the drawings, like parts in related Figures areidentified by like numbers. The terms appearing earlier in thespecification and in the description of the drawings are describedhereafter in the disclosure.

MODES FOR CARRYING OUT THE INVENTION

FIG. 1 represents a parenteral delivery system provided by the inventionand designated by the numeral 10. System 10 comprises a primarycontainer 11 formed of a flexible, or a semi-rigid preferablytransparent plastic, such as a non-toxic polyolefin, polyvinyl chlorideor the like. Primary container 11 is a large volume parenteral, LVP,container and it contains a medical fluid 12 adapted for parenteral,intravenous or other therapy. Medical liquid 12 in container 11 will betypically a sterile solution, such as an aqueous solution of dextrose,electrolytes, or saline. Container 11, in the embodiment illustrated, isnon-vented, the medical fluid is at atmospheric pressure, and thecontainer collapses as it empties of medical fluid 12. Container 11usually is adapted to be hung neck-down from a hanger 13 by a bib orhole 14 that connects, or is integrally formed as part of container 11.Container 11, at its end distant from its hanging end, that is, at itsneck end, has an administration port adapted for receiving a primaryfluid path.

The primary path is used to deliver medical fluid 12 by parenteraltherapeutic system 10 to a patient. The primary path is sterile,pyrogen-free, and disposable. The primary path comprises the componentsdescribed hereinafter, and it connects with port 15 of container 11.Port 15 can be a diaphram in container 11, now shown, or port 15 can bean adapter for receiving a hollow connector 16. Connector 16 is made toreceive end 17 of drip chamber 18. Drip chamber 18 is used to trap airand it also permits, in cooperation with regulator clamp 19, adjustmentof the rate of flow of medical fluid 12 from container 11 as the flowproceeds dropwise. An outlet 20 of drip chamber 18 is connected to oneend of a primary tube 21 that passes through regulator clamp 19 forpinching its internal diameter to regulate flow in cooperation with dripsight chamber 18. The other end of primary tube 21 connects to a valve22, beyond which common tube 23 connects from valve 22 to an adapterneedle assembly 24 that is inserted, for example, into the vein of awarm-blooded animal.

System 11 further comprises a secondary fluid path, which secondary pathconsists of a secondary container 26 or minibag formed of a flexible, ora semi-rigid preferably transparent plastic, such as a non-toxicpolyolefin, polyvinyl chloride or the like. Secondary container 26 is asmall volume parenteral, SVP, container and it contains a medical fluid27 adapted for parenteral, intravenous or other therapy. Medical fluid27 is a pharmaceutical vehicle for parenteral administration, that is,it is a pharmaceutical carrier for a drug that is to be administered toa recipient. Container 26, in the embodiment illustrated, is non-vented,medical fluid 27 is at atmospheric pressure, and the container collapsesas it empties of medical fluid 27. Container 26 is adapted to be hungneck-down from a hanger 13 by a bib or hole 28 that connects, or isintegrally formed as a part of container 26. Container 26, at its enddistant from its hanging end, that is, at its neck end, has anadministration port adapted for receiving a secondary fluid path.

The secondary fluid path provided by the invention is used to delivermedical fluid 27 to which a drug is added to a patient. The secondarypath is sterile, pyrogen-free and disposable. The secondary pathcomprises the components describer hereinafter, and it connects withport 29 of container 26. Port 29 can be a diaphram in container 26, notshown, or port 29 can be an adapter for receiving a hollow connector 30.Connector 30 is made to receive end 31 of drip chamber 32. Drip chamber32 is used to trap air and it also permits, in cooperation withregulator clamp 33, adjustment of the rate of flow of medical fluid 27from container 26 as the flow proceeds dropwise. An outlet 34 of dripchamber 32 is connected to one end of a segment of secondary tube 35passing through regulator clamp 33 for pinching its internal diameter toregulate flow in cooperation with sight drip chamber 32. The other endof secondary tube 35 connects to an agent formulation chamber 36.Regulator clamp 33 is used for governing the flow of fluid into an agentformulation chamber 36. Formulation chamber 36 is made of glass orplastic, and it is preferably transparent. Formulation chamber 36 canhave any shape adapted for use in a parenteral therapeutic system, andit is preferably round and its length exceeds its width. The end ofsecondary tube 35 mates snugly with end cap 37 of chamber 36. The end ofthe secondary tube can fit into cap 37 or it can slide over a tubereceiving member of cap 37 to form an air-tight, leak-proof chamber forcontaining at least one beneficial agent, or a delivery device. Chamber36 optionally is equipped with a release rate controlling membrane, notshown in FIG. 1, for example a microporous membrane or the like, thatgoverns the rate of release of agent solution from chamber 36. A releaserate controlling membrane can rest on a sintered glass supportintegrally made into the chamber, optionally a membrane can be sealedadhesively to the inside wall of chamber 36, fused thereto, be supportedby the wall of the chamber pinched inwardly, rest on a rim in thechamber, or it can be supported or suitably fixed to end cap 38positioned in chamber 36. A segment of secondary tube 39 conveys agentsolution from chamber 36 to valve 22. A regulator clamp 40 is providedon tube 39 as an aid in governing the flow of agent solution from theformulation chamber. Regulator clamps 40 can be used alone, incooperation with clamp 33, in cooperation with valve 22, and both incooperation with valve 22 for governing fluid flow and agent solutionflow through the secondary path. Valve 22, in a presently preferredembodiment, is a two position valve. Agent solution is conveyed fromvalve 22 through common tube 23 to needle assembly 24 for administrationto a recipient.

In operation, valve 22 in one position permits the passage of a drugsolution from chamber 36 to flow into common tube 23, whileconcomitantly stopping flow via tube 21; in its alternate secondposition, valve 22 stops flow of fluid in tubes 35 and 39, but it allowsflow in tube 21. When valve 22 is in its first position, the flow ofmedical fluid reaches the patient at a rate determined by the setting ofregulating clamp 33 with clamp 40 opened to flow; when valve 22 is inits second position, the flow of medical fluid reaches the patient at arate determined by the setting of flow regulating clamp 19. During theintervals of time valve 22 is in its second position, drug formulationproceeds in the presence of fluid in chamber 36 and its releasecontinues from formulation chamber 36 into tube 39, but it cannot reachthe patient, and so it accumulates in chamber 36 and tube 39. When valve22 is switched to its first position, accumulated drug formulationsolution in chamber 36 and tube 39 enters the patient, the quantity ofwhich is governed by the following pharmacodynamic expression: ##EQU1##wherein t_(j) equals the time valve 22 is switched from position 1 toposition 2; t_(k) equals the time valve 22 is switched from position 2to position 1; t_(L) equals the time valve 22 can be switched fromposition 1 back to position 2; and R₁ (t) equals the rate at whichformulation chamber 36 prepares and releases drug in solution; R₂ (t) isthe rate at which the formulation chamber prepares drug solution duringfree flow of intravenous fluid. The rate at which agent reaches apatient when valve 22 is switched to position 1, is related to the flowregulation imposed by clamp 33 which preferably should be adjusted toallow flow to occur at a rate which insures that all accumulated agententers the patient. While the above system and its operation weredescribed with a representative manually operated valve, it is to beunderstood other valve systems are embraced by this invention. Forexample, electro-mechanical devices that automatically switch back andforth between positions 1 and 2 at preset time intervals are within thescope of this invention.

FIG. 2 illustrates another intravenous system 10 provided by theinvention. System 10 comprises a primary path having in combination acontainer 41 that is a reservoir of a pharmaceutically acceptable liquidand it has an internal venting tube 42 which allows air to entercontainer 41 as medical fluid is infused into a patient. Container 41 isa large volume parenteral of a sterile fluid intended for themodification and maintainment of physiological functions in a recipient.Container 41 is closed with a stopper, not shown, and it has a hole forventing tube 42. Container 41 is connected through a non-vented hollowspike adaptor 43 to a primary delivery path for sending medical fluidfrom container 41 through the path to a patient. Spike 43 is in fluidcommunication with a drip chamber 44, which as previously described, ismade preferably of a see through material, such as a glass or plasticfor visibly counting the number of drops that pass through said dripchamber over unit time. Medical fluid leaves drip chamber 44 through asection of a primary tube 45 that passes through a flow regulator clamp46, that is used for regulating fluid flow from container 41, and forconveying fluid through tube 45 to two-way valve 49, and hence fromvalve 49 through fluid communicating common tube 47 and needle assembly48 to a recipient.

System 10 of FIG. 2 also comprises a secondary path consisting ofcontainer 50 that is a means for storing a pharmaceutically acceptableliquid. Container 50 has an internal venting tube 51 for letting airenter container 50 as liquid leaves the container. Container 50 is aminicontainer or a minibottle and it holds about 100 to 250 millilitersof liquid that is used for continuous drug transport, or forintermittent drug transport to a recipient. Container 50 is closed witha stopper, not shown, and it has a hole for venting tube 51. Container50 is connected through a non-vented hollow spike adaptor 52 to asecondary delivery system for sending medical liquid from container 50containing a drug through the secondary path to a patient. Spike 52 isin fluid communication with a drip chamber 53 designed for counting thenumber of drops that pass through said drip chamber over time. Medicalfluid leaves drip chamber 53 through a section of secondary tube 54 thatpasses through a flow regulator valve 57 that is used for regulatingliquid flow from container 51. Secondary tube 54 passes through clamp 57and it can be used as an on-off, or a volume flow regulator foradmitting fluid into an agent formulation chamber 58. Agent formulationchamber 58 is as described earlier comprised of a wall formed of a fluidimpermeable material that surrounds an internal space for housing adosage unit amount of a beneficial agent, or a delivery device. Chamber58 has a known volume and preferably a volumetric scale thereon forindicating the volume of fluid in said chamber. Chamber 58 has an end 59adapted for receiving incoming tube 54 and fluid from container 50, andit has an end 60 adapted for receiving outgoing tube 61. Tube 61 conveysfluid carrying the beneficial agent from chamber 58 to valve 49, andthence through fluid communicating common tube 47 to needle assembly 48,and to the recipient.

In operation, parenteral delivery system 10 of FIG. 2 is used likeparenteral delivery system 10 of FIG. 1. That is, system 10 of FIG. 2can be used (1) for administering a medical fluid that is free of agentby closing regulator 57, opening regulator 46 and positioning valve 49to let fluid flow from tube 45 and into tube 47; (2) for administeringcontinuously a medical fluid containing a beneficial agent by closingregulator 46, opening regulator 57 to permit fluid to flow throughformulation chamber 58 wherein the agent is added to the fluid, andpositioning valve 49 to let fluid flow through tube 61 and into tube 47;and (3) for administering at a selected dosing time a given volume offluid containing a known amount of agent by (a) permitting fluid to flowthrough the secondary path while setting valve 49 in closed position forthe secondary path, (b) permitting a known volume of fluid to enter theformulation chamber, which volume is ascertained by reading the meniscusagainst the volumetric scale on the chamber, and closing regulator clamp57 to stop the flow of additional fluid into the formulation chamber,(c) formulating the agent formulation in the chamber by dissolving agiven amount of agent present in the chamber, or delivered by a devicetherein, in the known volume of fluid, which amount of agent solubilityin the fluid dissolved over time, and (d) dosing a recipient with theagent solution whenever desired by positioning valve 49 to let it flowfrom the formulation chamber.

FIG. 3 represents a parenteral delivery system provided by the inventionand designated by the numeral 10. System 10 of FIG. 3 illustrates avented-type system that requires air to operate. System 10 comprises aglass container 65, suitably sealed with a rubber stopper and itcontains a medical fluid acceptable for parenteral including intravenousadministration. Container 65 is supported in delivery position bysupport 66, and air enters container 65 via air filter 67 connected tocontainer 65 through spike 68 that is hollow and pierces the rubberclosure of container 65. The other point of spike 68, not seen, enters adrip chamber 69 and it conveys medical fluid from container 65 into dripchamber 69. Drip chamber 69 is connected to a primary fluid path 70formed of a medical grade tubing that conveys medical fluid to needle71. A roller valve clamp 72 is provided on fluid path 70 for restrictingthe internal diameter of primary path 70 for regulating the flow offluid through primary path 70. System 10 of FIG. 3 also comprises asecondary fluid path 73 that joins a common path 75 at branch coupler74. Branch coupler 74 can be made as a Y-type connecting tube forreceiving primary path 70, secondary path 73 and common path 75.

The secondary path comprises a container 76 that is a minicontainer or aminibottle formed of glass, and suitably sealed with a rubber stopper,not visible, and it contains a medical fluid acceptable for parenteralincluding intravenous administration. Container 76 is supported indelivery position by support 66, and air enters container 76 through afilter 77 connected to container 76 through spike 78, which spike ishollow and pierces the rubber closure of container 76. The other pointof spike 78, not seen, enters a drip chamber 79 and it conveys medicalfluid from container 76 into drip chamber 79. Drip chamber 79 isconnected to a secondary fluid path 73 formed of a medical grade tubingthat conveys medical fluid transporting a beneficial agent to needle 71.A roller valve clamp 80 is provided on secondary fluid path 73 forrestricting the internal diameter of secondary path 73 for regulatingthe flow of fluid through the secondary path into agent formulationchamber 81. Agent formulation chamber 81 is sized and adapted for use inparenteral delivery system 10. Agent formulation chamber 81 isself-contained, self-priming, self-powered and amenable to low costmanufacture. Formulation chamber 81 is lightweight and disposable and itcomprises a wall 82 that surrounds and defines an internal lumen orspace 83. Formulation chamber 81 has an inlet 84 for receiving secondarypath 73 and it has an outlet 85 also adapted for placing chamber 81 insecondary path 73. Chamber 81 is made of glass, plastic or the like, andas illustrated it is made of a transparent material for viewing itsstructure. Chamber 81 can house a beneficial agent or an agent deliverydevice. An agent formulation formed in chamber 81 leaves chamber 81through secondary path 73, couple 74 and into common path 75 forinfusion into a recipient.

The agent in formulation chamber 81 can be in any pharmaceutical statethat forms an agent formulation with a medical fluid that enters chamber81, and the use of chamber 81 with an agent therein does not require anyreconstitution, or admixture prior to use. An agent formulation formedin chamber 81 leaves the chamber through secondary path 73 and it enterscommon path 75 for administration to an animal, including a humanpatient, through needle 71. Exemplary pharmaceutically acceptable formsthat can be used in chamber 81 include solid, crystalline,microcrystalline, particle, pellet, granules, powder, tablet,spray-dried, lypohilized, forms that dissolve or undergo disintegrationand dissolution in the presence of a parenteral fluid includingintravenous fluids, compressed forms that undergo disintegration anddissolution in the presence of a fluid such as compressed, compressedpowders, compressed granules, friable layers of agent, and/or the like.Agent formulation chamber 81 generally will store an amount of agent forexecuting a prescribed therapeutic or beneficial program. That is, anamount of agent for the preprogrammed, delivery of a therapeutically ora beneficially effective amount of the agent to produce a therapeutic ora beneficial result. Agent formulation chamber 81 generally will have acapacity of from about 10 milliliters to 250 milliliters of fluid ormore, and it can house from 5 milligrams to 20 grams of agent or more.The expression beneficial agent, as used herein, generically denotes anysubstance that produces a therapeutic or a beneficial result, such as adrug, a carbohydrate, an electrolyte and/or the like. The term fluid orliquid denotes a fluid, or a liquid that can be administeredparenterally including intravenously, comprising pharmaceuticallyacceptable fluids that are also a pharmaceutically acceptable carrierfor an agent, such as water, isotonic saline, Ringer's lactate, and thelike. The term formulation, and agent formulation as presently usedherein, generically indicates the beneficial agent is formulated, mixed,added, dissolved, suspended, solubilized, formulated into a solution,carried and/or the like in or by the fluid in a physical-chemical formacceptable for parenteral including intravenous administration. The flowof medical fluid into formulation chamber 81 can be started, stopped orregulated by clamp 80 that permits tube 73 to remain opened, shut orpartially obstructs the passage of fluid through tube 73, andcorrespondingly the flow of agent solution likewise can be governed fromchamber 81.

The delivery device housed in formulation chamber 81 releases an agentat a rate controlled by the device. The agent, on its release, isformulated in the chamber with fluid that is a pharmaceuticallyacceptable carrier for the agent into a parenteral including intravenousadministrable agent formulation, such as a drug solution. Devices thatcan be used for this purpose are those that release an agent bydissolution, diffusion or osmotic mechanism, or by otherphysical-chemical mechanism that produces an agent formulation. Theamount of agent in a formulation made in chamber 81 can be a traceamount to a saturating amount. The delivery devices, in one presentlypreferred embodiment are devices that cease releasing agent or shutthemselves off in the presence of a saturated agent formulation, that isa saturated solution.

In operation, parenteral delivery system 10 as illustrated in FIG. 3 canbe used by a physician, a nurse, or a practitioner in a hospital settingas follows: (1) for administering a medical fluid by adjusting regulatorvalve 80 to prevent the flow of fluid into formulation chamber 81, thusassuring that fluid will flow through primary path 70 and into skinpiercing means 71; (2) for administering a medical fluid containing abeneficial agent by adjusting regulator valve 72 to prevent the flow offluid through primary path 70, thereby directing the flow of fluid fromsecondary path 73 through opened valve 80 and into formulation chamber81, with agent formulation leaving chamber 81 through tube 73, union 74,tube 75 and into skin piercing means 71; and (3) for administering anamount of agent in a known volume of fluid arrived at by regulatingfluid flow through valve 72 and regulating fluid flow through valve 80and its accompanying flow through chamber 81, which fluid in bothinstances mixes into a common fluid at coupling 74 for its subsequentadministration to a recipient. The operations provided by thisembodiment of the invention makes available continuous and interruptedagent administration, and intervals of agent-free fluid administration.

The performance of a parenteral delivery system used for the purpose ofthe invention, also can be described mathematically in terms of thephysical and chemical functionality of the parenteral system. Generally,parenteral systems encompassed by this invention are those for whichQ_(R) ≦0.1Q_(KVO), wherein Q_(KVO) is the flow of fluid required tomaintain flow into the veins of an animal in which the flow pathterminates, by needle or catheter. This flow is referred to as the "keepvein open", rate Q_(KVO), and it typically is for an adult patient about10-20 drops per minute, or 0.5-1.0 ml per minute. The symbol Q_(R) isthe maximum rate of fluid flow needed for the parenteral delivery systemto deliver a solution at its label rate. Thus, parenteral systems foradult use require less than 0.05-0.1 ml/min to achieve label deliveryrate, and show independence of delivery rate from flow at all higherflows are encompassed by this invention. Delivery systems for pediatricuse will have a lower absolute limit, but still satisfy the generalcriterion Q_(R) ≦0.1Q_(KVO).

FIG. 4 depicts a formulation chamber 86 housing a delivery device thatcan be used in the secondary path of the parenteral delivery system ofFIGS. 1 to 3. The formulation chambers described in this specificationare the invention disclosed and claimed by Felix Theeuwes in copendingpatent applications Ser. No. 310,047, filed on Oct. 9, 1981, issued asU.S. Pat. No. 4,511,353, on Apr. 16, 1985, and Ser. No. 312,491, filedon Oct. 19, 1981. Both of these applications are assigned to the ALZACorporation of Palo Alto, Calif., the assignee of this patentapplication.

FIG. 4 depicts formulation chamber 86, housing a delivery device. TheFigure is enlarged for illustrating its components. Turning to FIG. 4 indetail, chamber 86 is seen comprising a wall 87 that has a sectionremoved for viewing its internal space 88. Chamber 86 has an inlet 89adapted and sized for placing chamber 86 into the secondary path of aparenteral therapy system, and it has an outlet 90 also adapted andsized for placing chamber 86 in the system. Inlet 89 and outlet 90 canbe optionally a female for receiving a tube, not shown, a rubber closurethat can be pierced by a needle attached to an incoming and outgoingtube, or any other suitable means adapted for placing chamber 86 in aparenteral system. In chamber 86 of FIG. 4, the chamber is seencomprising a pair of caps that constitute inlet 89 and outlet 90. Thecaps fit into the chamber and they are made of self-sealing rubberthrough which a needle or a hollow spike can be inserted, or of rubberwith a predrilled hole covered by a latex disc through which thesecondary path can be inserted for establishing fluid communication withthe inside 88 of chamber 86. The delivery device 91 illustrated in FIG.4 is an osmotic rate-controlled solid dosage delivery form as describedby patentee Felix Theeuwes and Takeru Higuchi in U.S. Pat. No.3,845,770. The osmotic device 91 seen in opened section comprises asemipermeable wall 92, such as cellulose acylate, cellulose diacylate,cellulose triacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, that surrounds and forms an agent or drug compartment 93.Compartment 93 contains an agent formulation 94, represented by dots,which formulation exhibits an osmotic pressure gradient across wall 92of device 91 against fluid in chamber 86. The agent formulation cancomprise an agent that exhibits an osmotic pressure gradient, or theagent formulation can comprise an agent mixed with an osmoticallyeffective solute, such as sodium chloride, potassium chloride and thelike, that exhibit an osmotic pressure gradient substantially greaterthan the fluid in chamber 86. A passageway 95 extends throughsemipermeable wall 92 and communicates with compartment 93 and theexterior of device 91. In operation, fluid enters into chamber 86 and isimbibed through the semipermeable wall of device 92 into compartment 93in a tendency towards osmotic equilibrium at a rate determined by thepermeability of the wall and the osmotic pressure gradient across thewall, thereby producing a solution in compartment 93 that is dispensedthrough passageway 95 at a time controlled by device 91 over a prolongedperiod of time. The delivery of agent formulation from device 91 forhomogenously blending with fluid in chamber 86, is controlled in thisembodiment by device 91 and it is essentially independent of the rate offluid flow through chamber 86. Device 91 maintains its physical andchemical integrity throughout its releasing history. In FIG. 4, theopened-section designated by the numbers 5-11, illustrates deliverydevices that can be used for the present purpose in the formulationchamber. A description of the devices follows in FIG. 5 to FIG. 11hereafter.

FIG. 5 depicts another device 96 for delivering an agent into aparenteral delivery system including an intravenously acceptable fluidthat enters a formulation chamber. Device 96 is illustrated inopened-section and it comprises an inner mass transfer conductor 97,illustrated as a solid core and formed of a polymeric material such ascured polydimethylsiloxane, with agent 98 dispersed therethrough.Surrounding mass transfer conductor 97 is a release rate controllingmembrane 99, preferably formed of a polymeric material, such aspolyurethene. Both conductor 97 and membrane 99 are permeable to thepassage of agent 98 by diffusion, that is, agent can dissolve in anddiffuse through conductor 97 and membrane 99. However, the permeabilityof conductor 97 is greater than that of membrane 99, and membrane 99thus acts as the rate controlling member for agent release from device96. Device 96 maintains its physical and chemical integrity throughoutthe period of drug delivery. Delivery device 96 is disclosed in U.S.Pat. No. 3,845,480.

FIG. 6 illustrates a delivery device 100 designed for use in aformulation chamber for delivering an agent at a rate controlled bydevice 100 into a fluid that enters the chamber. Device 100 is seen inopened-section and it comprises a reservoir 101 formed of a liquid masstransfer conductor, such as a medical oil carrier, permeable to thepassage of agent 102, such as the drug phenobarbital. Reservoir 101 issurrounded by a wall 103 formed of a release rate controlling materialpermeable to the passage of agent 102, such as a polyolefin. The rate ofpassage of agent 102 is lower through membrane 103 than the rate ofpassage through conductor 101, so that agent released by wall 103 is theagent release rate controlling step for releasing agent 102 from device100. Device 100 maintains its physical and chemical integrity throughoutits release history. Delivery device 100 is disclosed in U.S. Pat. No.3,993,073, which patent is incorporated herein by reference.

FIG. 7 illustrates another device 104 for use in a formulation chamberfor deliverying an agent into a liquid that enters a formulation chamberfor forming a parenteral agent solution including an intravenouslyacceptable agent solution. Device 104 is seen in opened-section and itcomprises a wall 105 surrounding a reservoir 106 containing agent 107.The reservoir is formed of a solid carrier permeable to the passage ofagent, such as cured polydimethylsiloxane containing diazepam. Wall 105is formed of a microporous material, for example a microporous polymermade by coprecipitation of a polycation and a polyanion. The release ofagent 107 is controlled by device 104, which device 104 maintains itsphysical and chemical integrity during the period of time it is in aformulation chamber. Device 104 is disclosed in U.S. Pat. No. 3,993,072,which patent is incorporated herein by reference.

FIG. 8 is a view of a device 108 for delivering an agent into a medicalfluid that enters the formulation chamber for forming in situ aparenteral or an intravenously acceptable agent formulation solution.Device 108 comprises a matrix 109 containing agent 110 distributedtherein. Matrix 109 is formed from a polymeric material that isnon-erodible and it is permeable to the passage of agent by diffusionfor releasing agent over time, or it undergoes relaxation and releasesagent 110 over time. The matrix can possess any shape such as rod, discand the like that fits into a formulation chamber. The polymers includepolyolefins such as polyethylene containing an agent such as musclerelaxants and the like. Materials useful for manufacturing the devicesare disclosed in U.S. Pat. No. 3,921,636.

FIG. 9 is a view of a delivery device 111 for delivering a beneficialagent into a fluid that enters the formulation chamber. Device 111 isformed of a microporous polymeric matrix 112 containing agent 113distributed therethrough. Matrix 112 is formed of a non-toxic, inertpolymer, that is non-erodible and has a plurality of micropores forreleasing agent 113 at a controlled rate to fluid entering theformulation chamber. Microporous materials useful for the presentpurpose are disclosed in U.S. Pat. Nos. 3,797,494 and 3,948,254.

FIG. 10 illustrates a delivery device 114 for delivering a beneficialagent into a medical fluid that enters a formulation chamber. Device 114is seen in opened section and it comprises depots 115 of medicationsolute 115 dispersed in and surrounded substantially individually by apolymer wall 116 that is impermeable to the passage of medication soluteand permeable to the passage of fluid that enters the formulationchamber. Medication solute 115 released at a controlled rate by fluidbeing imbibed through the polymer into the depots 115 to dissolve thesolute in depot 115 and generate a hydrostatic pressure in the depots,which pressure is applied against the wall of the depot thereby formingapertures that release the medication at a controlled rate over time.Polymer 116 is non-erodible, and device 114 can be shaped as a matrix,rod, a disc, or like shapes. Procedures and materials useful formanufacturing the delivery system of FIG. 10 are described in U.S. Pat.No. 4,177,256.

FIG. 11 illustrates a device 117 useful for delivering a drug into amedically acceptable fluid passing through formulation chamber. Device117 is seen in opened view and it comprises an exterior wall 118 formedof a semipermeable polymer permeable to fluid and substantiallyimpermeable to the passage of drugs and solutes. A layer 119 of anosmotically effective solute, for example sodium chloride, is depositedon the inner surface of wall 118. Solute layer surrounds an innercontainer 120 formed of a flexible material that is impermeable tosolute and drug. Container 120 has a passageway 121 for delivering adrug 122 into a fluid present in the formulation chamber. Device 117dispenses drug by fluid permeating from the chamber through wall 118 tocontinuously dissolve drug solute 122 in a tendency towards osmoticequilibrium, thereby continuously increasing the volume between wall 118and container 120. This increase causes container 120 to continuouslycollapse and dispense drug 122 from device 117 at a controlled ratethrough passageway 121 to fluid passing through the formulation chamber.Osmotically powered agent dispensing devices are disclosed in U.S. Pat.Nos. 3,760,984 and 3,995,631.

The delivery devices described in FIGS. 4 through 11 can contain variousamounts of an agent, for example, from about 1 milligram to 20 grams, ormore. The devices can release an agent at a rate of 10 nanograms perhour up to 3 grams per hour, or more, into a formulation chamber forforming an agent solution with the medical fluid that enters thechamber. The formulation chamber can optionally be considered as acartridge, since they can be used in the secondary path once or replacedmany times. That is, the cartridge can be removed after all the agent isdelivered, or the cartridge can be replaced repeatedly each time afterthe device has delivered its agent. Thus, this mode of the invention canlead to intermediate or continuous therapy, in addition to theoperations described in FIGS. 1 to 3.

FIG. 12 depicts another formulation chamber 125 that can be used in aparenteral delivery system as seen in FIGS. 1 to 3. FIG. 12 illustratesformulation chamber 125 that is light weight, disposable and indicatedfor use for patients requiring parenteral administration of a drug or anagent solution. In FIG. 12, chamber 125 comprises a body 126 of tubeshape, and it has a pair of caps 127 and 128 that fit into body 126 forforming a closed chamber 125 for containing a fluid that enters chamber125. Caps 127 and 128 are preferably made of self-sealing rubber throughwhich a needle or a hollow spike can be inserted, or of rubber with apre-drilled hole, not shown, covered by a latex disc through whichcommunication can be made with the inside of chamber 125. Chamber 125comprises wall 130 with a section removed for depicting internal lumen131. Chamber 125 contains drug 129 that is soluble in parenterallyacceptable fluids that enter chamber 125, and in a presently preferredembodiment chamber 125 houses a film 132 formed of a material operablefor controlling the release of drug 129 in solution from chamber 125.Film 132, in a preferred embodiment, is formed of a release ratecontrolling microporous polymer such as polycarbonate, celluloseacetate, or ethylene-vinyl acetate copolymer and the like. The polymericfilm according to the practice of the invention is used for governingthe rate of drug solution release from chamber 125. Chamber 125 isillustrated with a film at its exit, and optionally it can have a filmat its inlet. In an embodiment of the invention, the film can be placedvertically in the formulation chamber to the side of the inlet portconfining the drug therein, with fluid passing through the film, forminga drug solution, and then returning to the fluid passing through theformulation chamber for eventual administration.

FIG. 13 illustrates a formulation chamber 133 that can be used in thetherapeutic systems described in FIGS. 1 to 3. Chamber 133 comprises awall 134 that surrounds and defines an internal lumen 135. A section ofwall 134 is removed for illustrating the structure of chamber 133.Chamber 133 comprises a pair of closures 136 and 137 that fit over wall134 for forming a closed chamber 133. The closures 136 and 137 each havea hollow member 138 and 139 that are preferably round for receiving atube that can slide into, or slide over receiving members 138 and 139,thereby permitting chamber 133 to establish fluid communication with theparenteral therapeutic system. FIG. 13 further illustrates agent 140 inparticle form, a release rate controlling polymeric film 141 and afilter 142. Filter 142 is a conventional filter with a pore size of 0.1micron to 5 micron, and more preferably 0.22 micron or 0.45 micron, forremoving bacteria and unwanted matter from a flowing solution.

The parenteral delivery system comprising the primary path and thesecondary path with the agent formulation chamber in the secondary pathcan be used for the administration of many beneficial agents especially,where it is desirable to administer by infusion, and more particularlyvia the intravenous, intra-arterial, intraperitioneal or subcutaneousroutes. For example, the delivery system can be used in one presentlypreferred embodiment, in intravenous fluid replacement, such asadministering plasma or saline and simultaneously or intermittentlyadministering a therapeutically effective amount of drug therewith; inanother embodiment as a method in intravenous electrolyte-balancereplacement, such as supplying sodium, potassium or chloride ions withdrug administered therewith to a patient in need of electrolyterestoration and an intravenous drug; and in a method of intravenousnutrition, such as supplying dextrose and concomitantly administering orperiodically administering a parenterally administrable drug to apatient in need of such therapies.

The novel and useful invention provides a system and method forobtaining the precise control of agent administration to a recipient.While there has been described and pointed out features of the inventionas applied to presently preferred embodiments, those skilled in the artwill appreciate that various modifications, changes, additions andomissions in the invention illustrated and described can be made withoutdeparting from the spirit of the invention.

We claim:
 1. A parenteral delivery set for administering a beneficialagent formulation to a warm-blooded animal, the delivery setcomprising:(a) a primary tube for the flow of a parenterally acceptablefluid therethrough; (b) a secondary tube for the flow of a parenterallyacceptable fluid therethrough; (c) a formulation chamber incommunication with the secondary tube, the formulation chambercomprising:(1) a wall that surrounds an internal space; (2) an inlet forletting fluid enter the formulation chamber; (3) a beneficial agentdelivery device in the formulation chamber, the delivery devicecomprising a matrix formed of a microporous material, and a beneficialagent distributed in the microporous material; (4) an outlet for lettingan agent formulation exit the formulation chamber; and, (d) a commontube in communication with the primary tube for receiving fluid from theprimary tube, and in communication with the secondary tube for receivingagent formulation from the secondary tube.
 2. The parenteral deliveryset for administering the beneficial agent formulation according toclaim 1, wherein a drip chamber is in communication with the formulationchamber.
 3. The parenteral delivery set for administering the beneficialagent formulation according to claim 1, wherein a drip chamber is incommunication with the secondary tube.